Synthesis and biological evaluation of novel 1,2,3,4-tetrahydro-β-carboline derivatives as potential antibacterial agents

The quest for novel Antibacterial agents is imperative in the face of escalating Antibiotic resistance. Naturally occurring tetrahydro-β-carboline (THβC) Alkaloids have been highlighted due to their significant biological derivatives. However, these structures have been little explored for Antibacterial drugs development. In this study, a series of 1,2,3,4-THβC derivatives were synthesized and assessed for their Antibacterial prowess against both gram-positive and gram-negative bacteria. The compounds exhibited moderate to good Antibacterial activity, with some compounds showing superior efficacy against gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA), to that of Gentamicin. Among these analogs, compound 3k emerged as a hit compound, demonstrating rapid bactericidal action and a significant post-antibacterial effect, with significant cytotoxicity towards human LO2 and HepG2 cells. In addition, compound 3k (10 mg/kg) showed comparable anti-MRSA efficacy to Ciprofloxacin (2 mg/kg) in a mouse model of abdominal Infection. Overall, the present findings suggested that THβC derivatives based on the title compounds hold promising applications in the development of Antibacterial drugs.

1,2,3,4-tetrahydro-β-carboline; Antibacterial drugs; Bactericidal activity; Cytotoxicity; Structural activity relationship.